Alzheimer's Disease Drug Candidates Research Articles

Isobavachalcone ameliorates cognitive deficits, and Aβ and tau pathologies in triple-transgenic mice with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects 50 million people worldwide. The current medicines have modest benefits in preventing or curing AD. Thus, it is urgent to discover drugs with the potential to change the progression of the disease. The primary clinical symptoms are memory loss and anxiety, while the critical pathological characteristics are Aβ plaques and hyperphosphorylated tau tangles. In this study, isobavachalcone (ISO), isolated from Psoralea corylifolia, was administered to 3×Tg-AD mice. It has been shown that this compound could significantly improve anxiety, memory and recognition deficits in the AD mice, attenuate the accumulation of Aβ oligomers, reduce the hyperphosphorylation of tau, and prevent the production of tau filaments. The metabolomic analysis implicates that the most probable pathways affected by ISO were bile secretion, tyrosine metabolism, and purine metabolism. In summary, ISO possesses the potential for further development as a drug candidate for AD.

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models.

Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells.Methods: A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity.Results: C004019 induced a robust tau clearance via promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance in vivo. Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions.Conclusions: The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both in vitro and in vivo, which provides a promising drug candidate for AD and the related tauopathies.

A chemical biology approach to identifying molecular pathways associated with aging.

The understanding of how aging contributes to dementia remains obscure. To address this problem, a chemical biology approach was used employing CAD031, an Alzheimer's disease (AD) drug candidate identified using a discovery platform based upon phenotypic screens that mimic toxicities associated with the aging brain. Since CAD031 has therapeutic efficacy when fed to old symptomatic transgenic AD mice, the chemical biology hypothesis is that it can be used to determine the molecular pathways associated with age-related disease by identifying those that are modified by the compound. Here we show that when CAD031 was fed to rapidly aging SAMP8 mice starting in the last quadrant of their lifespan, it reduced many of the changes in gene, protein, and small molecule expression associated with mitochondrial aging, maintaining mitochondria at the younger molecular phenotype. Network analysis integrating the metabolomics and transcription data followed by mechanistic validation showed that CAD031 targets acetyl-CoA and fatty acid metabolism via the AMPK/ACC1 pathway. Importantly, CAD031 extended the median lifespan of SAMP8 mice by about 30%. These data show that specific alterations in mitochondrial composition and metabolism highly correlate with aging, supporting the use AD drug candidates that limit physiological aging in the brain.

Pharmacological exploration of traditional plants for the treatment of neurodegenerative disorders.

Alzheimer's disease (AD) is clinically characterized as memory deficits, altered behavior and impaired cognitive functions. The most important risk factor for AD is aging and mounting. Evidences suggested in different studies that traditionally used plants in Asia, China, and Europe significantly affect aging and AD involved neurodegeneration pathways. Research into ethnobotanicals for impaired memory and cognition has been burgeoned in last decades. The inclusion and exclusion criteria for the plant selection were based on reputed herbs recommended for treatment of neurological disorders and their scientific validation to cure neurodegenerative disorders. A range of traditional plants imparts effects via acetylcholinesterase activity, β-amyloid peptide formation in plaques, neurotrophic factors and through antioxidant activity. On one side preclinical investigations identified promising drug candidates for AD, on the other side, clinical evidences are still pending. Presently, according to WHO, around more than 80% world population relay on natural remedies to cure their health related issues. Plants contain rich source of primary and secondary metabolites for improving health problems. Pharmaceutical industry is facing intriguing challenges like elevated cost and unendurable risk management due to the high burden of neurodegenerative disorders. A significant shift of drug discovery is being witnessed from synthetic moieties to herbal formulation.

Modulation of Amyloid-β42 Conformation by Small Molecules Through Nonspecific Binding.

Aggregation of amyloid-β (Aβ) peptides is a crucial step in the progression of Alzheimer's disease (AD). Identifying aggregation inhibitors against AD has been a great challenge. We report an atomistic simulation study of the inhibition mechanism of two small molecules, homotaurine and scyllo-inositol, which are AD drug candidates currently under investigation. We show that both small molecules promote a conformational change of the Aβ42 monomer toward a more collapsed phase through a nonspecific binding mechanism. This finding provides atomistic-level insights into designing potential drug candidates for future AD treatments.

JBPOS0101 attenuates amyloid-β accumulation and memory loss in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) in the brain. Defects in Aβ clearance or the interference of Aβ homeostasis could result in Aβ aggregation. JBPOS0101 has been studied for its antiepileptic activity. It showed a neuroprotective effect and prevented memory deficits in lithium-pilocarpine-induced status epilepticus rats. In this study, we tested the effect of JBPOS0101 in an AD model. We showed that JBPOS0101 attenuated the accumulation of Aβ in 5XFAD mouse brains. Moreover, the treatment of JBPOS0101 rescued the deficits in learning and memory in 5XFAD mice. These data suggest that JBPOS0101 could be a potential therapeutic drug candidate for AD.

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor.

Progressive dysfunction of cholinergic transmission is a well-known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aβ binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes. We developed a specific and quantitative time-resolved FRET (TR-FRET)-based binding assay for Aβ to α7nAChR and pharmacologically characterized this interaction. We demonstrated specific and high-affinity (low nanomolar) binding of Aβ to the orthosteric binding site of α7nAChR. Aβ binding was prevented and reversed by the well-characterized orthosteric ligands of α7nAChR (epibatidine, α-bungarotoxin, methylylcaconitine, PNU-282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU-120596 but not by the type I PAM NS1738. Our TR-FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs. This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer's Disease.

Finding a therapy for Alzheimer's disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates. Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain. This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal. Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction. Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.

Dementia treatment versus prevention

Alzheimer disease (AD) and dementia are becoming increasingly prevalent due to the aging of the global populations. Currently available treatment options, including acetylcholinesterase inhibitors and memantine, only have symptomatic effects and no drugs with disease-modifying properties are available. Research on the amyloid cascade indicates that amyloid-β (Aβ) clearance from the brain may be the main pathophysiological change in late-onset AD and the key driver of neurodegeneration, which ultimately results in progressive cognitive deterioration and dementia. Most new AD drug candidates target different aspects of Aβ clearance, eg, using passive anti-Aβ immunization, but so far, all efforts to develop more effective drugs have failed. In parallel, nonpharmacological prevention trials are being conducted to modify dementia risk associated with known epidemiological risk factors. Some initial results are promising, but replication across independent cohorts remains a challenge.

Can We Prevent Dementia and Not Prevent Neurons from Dying?

Neuronal death is the final step in the progression of preclinical Alzheimer's disease (AD) pathologies into clinically evident AD and its profound dementia. As such, a drug candidate proposed to be effective in AD must successfully prevent neuronal losses. The lack of preclinical demonstrated abilities to prevent neuronal programmed cell death may explain the recent failure of 300-400 AD drug candidates, identify a flaw in the Amyloid Hypothesis, and a risk for subsequent drug candidate interventions against AD. We propose that investigators use either animal models or small early translational clinical trials to test for AD drug candidates' efficacy against clinically critical features of the disease, such as prevention of neuronal death. Such stringent testing would more effectively shelter AD patients from being recruited into clinical trials that are destined to fail in Phase II or III.

Dementia treatment versus prevention

Alzheimer disease (AD) and dementia are becoming increasingly prevalent due to the aging of the global populations. Currently available treatment options, including acetylcholinesterase inhibitors and memantine, only have symptomatic effects and no drugs with disease-modifying properties are available. Research on the amyloid cascade indicates that amyloid-β (Aβ) clearance from the brain may be the main pathophysiological change in late-onset AD and the key driver of neurodegeneration, which ultimately results in progressive cognitive deterioration and dementia. Most new AD drug candidates target different aspects of Aβ clearance, eg, using passive anti-Aβ immunization, but so far, all efforts to develop more effective drugs have failed. In parallel, nonpharmacological prevention trials are being conducted to modify dementia risk associated with known epidemiological risk factors. Some initial results are promising, but replication across independent cohorts remains a challenge.

Old age-associated phenotypic screening for Alzheimer's disease drug candidates identifies sterubin as a potent neuroprotective compound from Yerba santa

Alzheimer's disease (AD) is the most frequent age-associated dementia with no treatments that can prevent or slow its progression. Since age is by far the major risk factor for AD, there is a strong rationale for an alternative approach to drug discovery based upon the biology of aging. Phenotypic screening assays that reflect multiple, age-associated neurotoxicity pathways rather than single molecular targets can identify compounds that have therapeutic efficacy by targeting aspects of aging that contribute to AD pathology. And, while the suitability of any single assay can be questioned, a combination of assays can make reliable predictions about the neuroprotective effects of compounds in vivo. Therefore, our lab has developed a combination of phenotypic screening assays that are ideally suited not only to identify novel neuroprotective compounds for the treatment of AD but also their target pathways, thereby potentially providing new therapeutic targets for disease treatment. Using these assays, we screened a large library of extracts from plants with identified pharmacological uses. Analysis of one of these extracts from the plant Yerba santa (Eriodictyon californicum) identified the flavanone sterubin as the active component and further studies showed it to be a potent neuroprotective and anti-inflammatory compound.

Geroneuroprotectors: Effective Geroprotectors for the Brain

Geroprotectors are compounds that slow the rate of biological aging and therefore may reduce the incidence of age-associated diseases such as Alzheimer's disease (AD). However, few have therapeutic efficacy in mammalian AD models. Here we describe the identification of geroneuroprotectors (GNPs), novel AD drug candidates that meet the criteria for geroprotectors.

Novel sulfamate derivatives of menthol: Synthesis, characterization, and cholinesterases and carbonic anhydrase enzymes inhibition properties.

Sulfamates have a large spectrum of biological activities including enzyme inhibition. Eight sulfamates derived from menthol (2a-h) were synthesized. Also, in the other section of this study, novel sulfamate derivatives of menthol were tested against some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carbonic anhydrase I and II enzymes (hCAs I and II). The newly synthesized novel menthol sulfamate and menthol carbonyl sulfamate derivatives showed Ki values in the range of 34.37 ± 8.17 to 53.40 ± 10.61 nM against hCA I, 12.91 ± 4.57 to 38.67 ± 6.22 nM against hCA II, 111.17 ± 52.36 to 522.86 ± 120.08 nM against AChE, and 50.01 ± 11.73 to 109.63 ± 50.08 nM against BChE. As a result, the novel menthol sulfamate and menthol carbonyl sulfamate derivatives can be promising Alzheimer's disease drug candidates and novel hCA I and hCA II enzymes inhibitors.

Characterization of the interactions between coumarin-derivatives and acetylcholinesterase: Examination by NMR and docking simulations.

Alzheimer's disease (AD) is one of the most common forms of dementia and a significant threat to the elderly populations, especially in the Western world. The rapid hydrolysis of the principal neurotransmitter into choline and acetate by acetylcholinesterase (AChE) at synapses causes the loss of cognitive response that becomes the real cause of AD. Therefore, inhibition of AChE is the most fundamental therapy among currently available treatments for AD. In this context, we designed and performed molecular recognitions studies of coumarin-based inhibitors towards AChE. STD NMR and Tr-NOESY applications were utilized to evaluate the binding epitope, the dissociation constant (KD) and bound conformations of these inhibitors within this inhibitor-AChE complex. Compound 1, which has a similar inhibition activity to tacrine (a current drug) led in this study as a stronger binder with KD = 30μM ,even greater than tacrine (KD = 140μM). Moreover, docking simulations mimic NMR results and provided evidence of synchronizing binding of compound 1 with three sites; the peripheral anionic site, the bottom of the gorge, and the catalytic site. Therefore, we envisioned from our experimental and theoretical results that coumarin-based inhibitors containing a piperidinyl scaffold might be a potential drug candidates for AD in the future.

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease

Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer’s disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides’ potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D-peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides’ potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The Food and Drug Administration has approved drugs (e.g., rivastigmine, donepezil, galantamine, and memantine) that at best provide marginal benefits, thus emphasizing the urgent need to explore other molecular entities as future drug candidates for AD. Looking at the wide pharmaceutical applications of heterocyclic compounds and particularly those containing benzofuran and indole ring systems, these molecular frameworks have drawn special attention from medicinal chemists for further evaluation in numerous diseases. This article focuses on the history and recent advances of benzofuran- and indole-based compounds as inhibitors of butyrylcholinesterase, acetylcholinesterase, γ-secretase, β-secretase, tau misfolding, and β-amyloid aggregation.

The development of a stochastic mathematical model of Alzheimer’s disease to help improve the design of clinical trials of potential treatments

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by a slow progressive deterioration of cognitive capacity. Drugs are urgently needed for the treatment of AD and unfortunately almost all clinical trials of AD drug candidates have failed or been discontinued to date. Mathematical, computational and statistical tools can be employed in the construction of clinical trial simulators to assist in the improvement of trial design and enhance the chances of success of potential new therapies. Based on the analysis of a set of clinical data provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI) we developed a simple stochastic mathematical model to simulate the development and progression of Alzheimer’s in a longitudinal cohort study. We show how this modelling framework could be used to assess the effect and the chances of success of hypothetical treatments that are administered at different stages and delay disease development. We demonstrate that the detection of the true efficacy of an AD treatment can be very challenging, even if the treatment is highly effective. An important reason behind the inability to detect signals of efficacy in a clinical trial in this therapy area could be the high between- and within-individual variability in the measurement of diagnostic markers and endpoints, which consequently results in the misdiagnosis of an individual’s disease state.

The mitochondrial ATP synthase is a shared drug target for aging and dementia.

SummaryAging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age‐associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α‐F1‐ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin‐dependent protein kinase kinase β (CAMKK2)‐dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age‐associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age‐associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.

Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?

IntroductionNeurodegenerative disorders have been a graveyard for hundreds of well-intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimer's disease (AD) share many overlapping pathologies and possible clinical links. MethodsWe searched the literature since 1995 using MEDLINE and Google Scholar for the terms concussion, AD, and shared neuropathologies. We also studied a TBI animal model as a supplement to transgenic (Tg) mouse AD models for evaluating AD drug efficacy by preventing neuronal losses. To evaluate TBI/AD pathologies and neuronal self-induced cell death (apoptosis), we are studying brain extracellular vesicles in plasma and (-)-phenserine pharmacology to probe, in animal models of AD and humans, apoptosis and pathways common to concussion and AD. ResultsNeuronal cell death and a diverse and significant pathological cascade follow TBIs. Many of the developing pathologies are present in early AD. The use of an animal model of concussion as a supplement to Tg mice provides an indication of an AD drug candidate's potential for preventing apoptosis and resulting progression toward dementia in AD. This weight drop supplementation to Tg mouse models, the experimental drug (-)-phenserine, and plasma-derived extracellular vesicles enriched for neuronal origin to follow biomarkers of neurodegenerative processes, each and in combination, show promise as tools useful for probing the progression of disease in AD, TBI/AD pathologies, apoptosis, and drug effects on rates of apoptosis both preclinically and in humans. (-)-Phenserine both countered many subacute post-TBI pathologies that could initiate clinical AD and, in the concussion and other animal models, showed evidence consistent with direct inhibition of neuronal preprogrammed cell death in the presence of TBI/AD pathologies. DiscussionThese findings may provide support for expanding preclinical Tg mouse studies in AD with a TBI weight drop model, insights into the progression of pathological targets, their relations to apoptosis, and timing of interventions against these targets and apoptosis. Such studies may demonstrate the potential for drugs to effectively and safely inhibit preprogrammed cell death as a new drug development strategy for use in the fight to defeat AD.